AKNet Update
New AK Treatment Options Making Headlines

Editor's Note:  In March 2004, imiquimod received FDA approval for the treatment of actinic keratoses.

Actinic keratoses (AKs), which now affect over 10 million Americans, have been in the news more and more in recent years. Much of this coverage focuses on treatment options. In 2002, diclofenac sodium gel made headlines when it received approval from the U.S. Food and Drug Administration (FDA) for treatment of AKs. Currently, 3 treatment methods are showing much promise in clinical trials:

• Imiquimod
• Photodynamic therapy (newer forms)
• Retinoids

Imiquimod: An Immunomodulator
Imiquimod belongs to a class of drugs called immunomodulators, which work by modifying the skin’s immune system to stimulate the body’s own rejection of pre-cancerous cells. Studies indicate that imiquimod, a topical cream, safely and effectively treats multiple AK lesions and is well tolerated by patients. Many of the patients participating in these studies achieved complete clearance.

The highest efficacy and fewest side effects were achieved when imiquimod was applied via cycle therapy—a form of treatment in which the medication is applied for a specified duration, stopped for a pre-determined amount of time and then resumed.

Researchers continue to look for the ideal regimen. Several studies required patients to apply the cream 3 times per week, and duration ranged from 4 to 12 weeks before patients stopped for a pre-determined amount of time. In a few studies, patients developed irritation when they applied the cream 3 times per week; however, when a rest period was given and patients resumed applying the cream only twice a week, imiquimod was well tolerated and cleared many lesions.

Overall, studies found that when the frequency is modified so that patients do not have adverse effects and cycle therapy is used, patients achieve significant reduction in the number of AKs, the medication is well tolerated, and imiquimod can be used on a long-term basis with good results. The studies are also finding that patients previously treated with the topical chemotherapy agent, 5-fluorouracil (5-FU), prefer imiquimod because the skin irritation from imiquimod is not as severe.

Imiquimod is FDA approved for the treatment of external genital and perianal warts.

Photodynamic Therapy: New Forms
Photodynamic therapy, already FDA approved for treatment of actinic keratoses, requires topical application of 5-aminolevulinic acid (ALA) to the lesions. This is followed by exposure to blue light after 14-to-18 hours. Modifications to this method are being investigated. One recent study modified the treatment method by: 1) Applying topical ALA to the lesions and areas around the lesions and 2) Reducing the incubation time from 14–18 hours to 1–3 hours. The treated areas were then exposed to blue light for the FDA-approved amount of time. Over 89% of the lesions cleared after one month, indicating that a shorter incubation time can be effective and that phototherapy may be used to treat not only AKs but accompanying photodamaged skin.

Another study substituted red light for blue light. At the conclusion of this study, 88% of the lesions were destroyed, and 91% percent of the investigators rated the cosmetic results as excellent. Additional studies are planned to evaluate use of different topical agents.

Retinoids: Prevention and Treatment
Current treatment methods for AKs focus on destroying the lesions. While effective, substantial health benefits could be gained from a method that not only treats AKs but prevents them. One class of drugs being investigated for this purpose is retinoids, which are already used to effectively treat acne and reduce signs of aging.

It is known that the oral retinoid, isotretinoin, is effective in preventing AKs; however, the high doses currently needed for prevention limit prescription to patients at high risk of developing skin cancer. When administered in such high doses, each patient must be closely monitored because serious side effects can occur.

Researchers believe that more tolerable retinoids may be within reach. Two topical retinoids-- adapalene and tretinoin--are being investigated in clinical trials to determine if they are effective in treating and preventing AKs. Findings indicate that topical forms of both adapalene and tretinoin may be effective.

In one clinical trial, 66% of patients who were treated with adapalene gel for 9 months saw a significant reduction in the number of AKs, and the medication was well tolerated. Since retinoids normalize abnormal skin growth, adapalene gel was also found to improve signs of photoaging, such as mottled skin and wrinkles. There is also evidence that adapalene may prevent squamous cell carcinoma, a form of skin cancer that can be life threatening. Similar results have been obtained for tretinoin.

Other Treatments
Research and development of treatment methods for AKs is ongoing. If you are being treated for AKs, be sure to ask your dermatologist about other treatment modalities that may be right for you.

References
Kang, S et al. “Assessment of adapalene gel for the treatment of actinic keratoses and lentigines: A randomized trial.” Journal of the American Academy of Dermatology 2003; 49: 83-90.

Persaud, A et al. “Imiquimod cream in the treatment of actinic keratoses.” Journal of the American Academy of Dermatology 2002; 47:S236-S239.

Tutrone, WD et al. “Topical Therapy for Actinic Keratoses, I: 5-Fluorouracil and Imiquimod.” Cutis 2003; Vol.71, No. 5:365-370.

Tutrone, WD et al. “Topical Therapy for Actinic Keratoses, II: Diclofenac, Colchicine, and Retinoids.” Ibid, 373-379.

Weinberg, JM. “Nature of the Beast,” Ibid, 343.

Yu, TC et al. “Actinic Keratoses—Surgical and Physical Therapeutic Modalities.” Ibid, 381-384.